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Metabolomic Profiling Diagnoses Inborn Errors of Metabolism at Higher Rate Than Traditional Approach

NEW YORK — Metabolomic profiling may be able to identify a higher number of inborn errors of metabolism among newborns than traditional screening, according to a new analysis.

A cross-sectional study compared data clinical samples from nearly 3,300 unrelated families that underwent traditional metabolic screening and ones that underwent metabolomic screening. According to a team led by Baylor College of Medicine researchers, metabolomic screening had a sixfold higher diagnostic rate than traditional metabolic screening, as reported in JAMA Network Open.

Newborn screening aims to identify inborn errors of metabolism early on as many such conditions are treatable, and early treatment can prevent irreversible effects of the conditions. Currently, the Recommended Uniform Screening Panel, or RUSP, recommends testing for 49 different metabolic conditions, with some state-to-state variation, but that list, the researchers noted, does not include all treatable inborn errors of metabolism.

"Just as genomic analysis has broadened the phenotypic spectrum of disease, so has untargeted metabolomics — both highlighting the breadth and complexity of human traits and disease," senior author Sarah Elsea, a professor of molecular and human genetics at Baylor, said in an email. "We only know what we know. If we do look beyond those limits, then we will never discover anything new, and we will not improve diagnosis, treatment, or quality of life."

The researchers' analysis compared two cohorts, one in which traditional screening was performed on samples from 1,483 unrelated families and one in which clinical metabolomic screening was performed on samples from 1,807 unrelated families. Traditional screening encompasses plasma amino acid testing, plasma acylcarnitine profiling, and urine organic acid testing and was performed at Baylor. Metabolomic profiling was performed in collaboration with the company Metabolon. Patients underwent testing at the request of their healthcare provider.

Within the traditional screening cohort, the researchers identified 159 families with biochemical abnormalities. Additional analyses using integrated clinical and genetic data ­— including targeted biochemical testing, exome sequencing, and more — confirmed a diagnosis for an inborn error of metabolism for 19 cases, with the analysis uncovering 14 different disorders within the cohort. Overall, the researchers reported a diagnostic rate of 1.3 percent for traditional screening.

For the metabolomic screening cohort, the researchers identified 912 metabolic abnormalities, which they classified into three categories: specific and diagnostic for an inborn error of metabolism, suggestive of one, or nonspecific. After undergoing the same integrative analysis as the other cohort, the researchers identified 128 cases of inborn error of metabolism. This, they reported, represents an overall diagnostic rate of 7.1 percent.

Of the 128 diagnoses made through metabolomic screening, 21 are included on the RUSP list but most were not. Those conditions include amino acidopathies, vitamin or cofactor deficiencies, and nucleic acid metabolism disorders, among a range of others. Further, the researchers noted that 26 of those 49 conditions are not covered by traditional screening and seven of them are currently treatable.

The findings suggested to the researchers that untargeted clinical metabolomics has a higher diagnostic rate when screening for inborn errors of metabolism and could have utility as a first-line screening tool for such conditions. They further added that it could be adopted in conjunction with genetic screening approaches.

They noted, though, that untargeted metabolomics has limitations, as it can only identify small molecules and not larger, complicated lipids or sugars, and that the identification of some molecules requires special extraction or preparation approaches.

Elsea and her colleagues are continuing to examine biomarkers to diagnose and monitor inborn errors of metabolism. "We are targeting additional rare and more common disorders to identify disease-specific biomarkers, utilizing this testing approach to monitor treatment and management of individuals with inborn errors of metabolism, and investigating other types of biological samples that may be required for diagnosis of some conditions," she added.